Stress reveals new destination for EGF receptor

Tomás, Alejandra; Futter, Clare E.

doi:10.1080/15384101.2015.1093432

Cited by 3 publications

(8 citation statements)

References 7 publications

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“…Recent advances have revealed that a wide variety of cellular stresses which activate the p38 MAP kinase (p38MAPK), ranging from common cancer therapies such as irradiation and cisplatin to pro-inflammatory cytokines, induce EGFR internalization and endosomal arrest independent of ligand binding, kinase activity, or ubiquitination (7, 8, 37). Stress-exposed EGFRs are sorted away from the ligand-dependent pathway to a distinct subset of stable multivesicular endosomes by a mechanism involving the WASP and Scar homologue (WASH) complex which regulates actin dynamics (38).…”

Section: Egfr Signaling and Traffickingmentioning

confidence: 99%

“…1) including the accessory protein Alix that is dispensable in the canonical ligand-induced EGFR trafficking pathway (35, 38). Interestingly, Alix also regulates the back-fusion of ILVs with endosomal limiting membranes which allows stress-exposed EGFRs to escape lysosomal degradation and recycle back to the plasma membrane when p38MAPK activity declines (7, 8, 40). Stress-exposed EGFRs can transduce signals after they have been internalized to endosomes through transactivation (38).…”

Section: Egfr Signaling and Traffickingmentioning

confidence: 99%

“…Many cellular stress stimuli activate p38MAPK leading to phosphorylation of specific serine residues in the cytoplasmic domain of EGFR (7, 8, 37) [Step 1]. Domain-specific polarity factors could either enhance uptake from the apical membranes [Step 2a], or alternatively inhibit uptake from BL membranes similar to physical interactions between EGFR and E-cadherin that limit ligand-induced EGFR internalization (68) [Step 2b].…”

Section: Figurementioning

confidence: 99%

“…Most studies documenting oncogenic EGFR-STAT3 signaling assume that this pathway is activated by autocrine growth factors released by tumor cells, or growth factors produced by non-malignant stromal and immune cells in the tumor microenvironment. However, recent evidence suggests that both intrinsic and therapy-induced cellular stressors trigger robust EGFR trafficking and signaling independent of extrinsic ligand (7, 8). Furthermore, these stress-induced EGR responses are associated with a survival advantage and resistance to therapeutics by mechanisms that are incompletely understood (7, 8).…”

Section: Introductionmentioning

confidence: 99%

“…However, recent evidence suggests that both intrinsic and therapy-induced cellular stressors trigger robust EGFR trafficking and signaling independent of extrinsic ligand (7, 8). Furthermore, these stress-induced EGR responses are associated with a survival advantage and resistance to therapeutics by mechanisms that are incompletely understood (7, 8). The goal of this review is to consider how EGFR signaling that is activated intracellularly independent of exogenous growth factor stimulation at the plasma membrane might contribute to the early evolution of triple-negative breast cancers (TNBCs) by activation of STAT3 signaling.…”

Section: Introductionmentioning

confidence: 99%

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Stress-induced EGF receptor signaling through STAT3 and tumor progression in triple-negative breast cancer

Balanis

Carlin

2017

Molecular and Cellular Endocrinology

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Elevated STAT3 activity is a hallmark of many epithelial carcinomas particularly in breast cancers where it is known to contribute to tumor progression through a variety of context-dependent biological responses. However, its role downstream of stress-exposed EGF receptors (EGFR) that are transactivated in endosomes independent of exogenous ligand has not been studied. This review discusses how STAT3 signaling induced by therapeutic stress in EGFR-driven triple-negative breast cancers (TNBC) might override normal epithelial homeostatic mechanisms and provide a survival advantage for tumor cells before they leave the primary tumor and spread to distant sites. Despite continued improvements in breast cancer treatment strategies, TNBC is still associated with poor prognosis and high risk of distant recurrence and death. Understanding EGFR-STAT3 signaling mechanisms regulating the earliest steps of tumor progression is a key to discovery of new targeted therapies against TNBC.

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Section: Egfr Signaling and Traffickingmentioning

confidence: 99%

Section: Egfr Signaling and Traffickingmentioning

confidence: 99%

Section: Figurementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Stress-induced EGF receptor signaling through STAT3 and tumor progression in triple-negative breast cancer

Balanis

Carlin

2017

Molecular and Cellular Endocrinology

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Accessory ESCRT‐III proteins are conserved and selective regulators of Rab11a‐exosome formation

Marie

Fan

Mason

et al. 2023

J of Extracellular Vesicle

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Exosomes are secreted nanovesicles with potent signalling activity that are initially formed as intraluminal vesicles (ILVs) in late Rab7‐positive multivesicular endosomes, and also in recycling Rab11a‐positive endosomes, particularly under some forms of nutrient stress. The core proteins of the Endosomal Sorting Complex Required for Transport (ESCRT) participate in exosome biogenesis and ILV‐mediated destruction of ubiquitinylated cargos. Accessory ESCRT‐III components have reported roles in ESCRT‐III‐mediated vesicle scission, but their precise functions are poorly defined. They frequently only appear essential under stress. Comparative proteomics analysis of human small extracellular vesicles revealed that accessory ESCRT‐III proteins, CHMP1A, CHMP1B, CHMP5 and IST1, are increased in Rab11a‐enriched exosome preparations. We show that these proteins are required to form ILVs in Drosophila secondary cell recycling endosomes, but unlike core ESCRTs, they are not involved in degradation of ubiquitinylated proteins in late endosomes. Furthermore, CHMP5 knockdown in human HCT116 colorectal cancer cells selectively inhibits Rab11a‐exosome production. Accessory ESCRT‐III knockdown suppresses seminal fluid‐mediated reproductive signalling by secondary cells and the growth‐promoting activity of Rab11a‐exosome‐containing EVs from HCT116 cells. We conclude that accessory ESCRT‐III components have a specific, ubiquitin‐independent role in Rab11a‐exosome generation, a mechanism that might be targeted to selectively block pro‐tumorigenic activities of these vesicles in cancer.

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Accessory ESCRT-III proteins selectively regulate Rab11-exosome biogenesis inDrosophilasecondary cells

Marie

Fan

Mendes

et al. 2020

Preprint

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Exosomes are secreted nanovesicles with potent signalling activity that are initially formed as intraluminal vesicles (ILVs) in multivesicular endosomes, which subsequently fuse with the plasma membrane. These ILVs are made in both late endosomes and recycling endosomes, the latter marked by the small GTPase Rab11 and generating exosomes with different cargos and functions. Core proteins within four Endosomal Sorting Complex Required for Transport (ESCRT) assemblies (0-III) play key sequential roles in late endosomal exosome biogenesis and ILV-mediated destruction of ubiquitinylated cargos through the endolysosomal system. They also control additional cellular processes, such as cytokinesis and other vesicle budding.By contrast, the functions of several accessory ESCRTs are not well defined. Here we assess the ESCRT-dependency of Rab11-exosomes, using RNA knockdown in Drosophila secondary cells (SCs) of the male accessory gland, which have unusually enlarged Rab11-positive compartments. Unexpectedly, not only are core proteins in all four ESCRT complexes required for Rab11-exosome formation, but also accessory ESCRT-III proteins, CHMP1, CHMP5 and IST1. Suppressing expression of these accessory proteins does not affect other aspects of cell morphology, unlike most core ESCRT knockdowns, and does not lead to accumulation of ubiquitinylated cargos. We conclude that accessory ESCRT-III components have a specific and potentially ubiquitin-independent role in Rab11-exosome generation, which might provide a target for blocking the pro-tumorigenic activities of these vesicles in cancer.

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Stress reveals new destination for EGF receptor

Cited by 3 publications

References 7 publications

Stress-induced EGF receptor signaling through STAT3 and tumor progression in triple-negative breast cancer

Stress-induced EGF receptor signaling through STAT3 and tumor progression in triple-negative breast cancer

Accessory ESCRT‐III proteins are conserved and selective regulators of Rab11a‐exosome formation

Accessory ESCRT-III proteins selectively regulate Rab11-exosome biogenesis inDrosophilasecondary cells

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